Mooradian, Meghan J.

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

Importance The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development. Objectives To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs. Design, Setting, and Participants This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025. Exposure Late-onset irAEs. Main Outcomes and Measures The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs. Results Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti–programmed death ligand 1 (PD-L1) and anti–programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti–PD-L1–based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti–cytotoxic T-lymphocyte–associated protein 4 ( P < .001). Patients receiving perioperative ICI therapy were significantly more likely to be admitted at the intermediate interval (16 of 68 [23.5%]) compared with those with metastatic disease (87 of 678 [12.8%]) ( P = .03). Timing of irAE was also significantly associated with active ICI exposure; among the patients presenting late, 7.4% (48 of 651) had received ICI therapy within the last 60 days compared with 26.4% (38 of 144) who had not had recent ICI exposure ( P < .001). Conclusions and Relevance The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.

9508 Background: Outcomes for pts with mMEL remain sobering despite access to available immunotherapies as the majority of pts are resistant or become refractory to checkpoint blockade with no approved treatments. CXCR1 and CXCR2 (CXCR1/2) signaling mediate myeloid immunosuppression and MEL growth, inversely correlating with anti-PD-1 response and pt survival. SX-682 is an oral allosteric inhibitor of CXCR1/2. As a single agent, SX-682 increases tumor CD8+ T cell infiltration and inhibits tumor growth in mouse MEL. Methods: This phase 1 dose-escalation with expansion trial (NCT03161431) evaluated pem and escalating doses of SX-682 (25 - 400 mg orally BID) in pts with mMEL in a 21-day cycle. Pts must have had progressive disease (PD) on prior anti-PD-1. Mucosal MEL and asymptomatic brain metastases were allowed. Escalation cohorts had a 21-day SX-682 monotherapy (MONO) run-in. Response assessment by RECIST 1.1 was every 2 cycles during combination (COMBO) treatment. Primary endpoint was safety: adverse events (AEs), dose-limiting toxicity (DLT) and maximally-tolerated dose (MTD). Secondary endpoints included objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + PR + stable disease [SD]) and overall survival (OS). Results: As of October 2023, 51 pts were enrolled and treated; median age of 65 (range 24-91), 55% male, 61% elevated LDH, 39% BRAF mutated. All pts received prior anti-PD-1, 37 (73%) received combined anti-PD-1 and anti-CTLA-4, and 23 (45%) had ≥ 3 prior therapies. Steady-state blood SX-682 was dose-proportional. No MONO DLT or MTD was identified. The 200 mg dose cohort was expanded in COMBO based on safety and pharmacodynamics: mg BID dose (n) = 25 (3), 50 (3), 100 (6), 150 (8), 200 (31). Any grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 75% and 43%, respectively, and discontinuation (DC) due to TRAEs in 20% (when uncomplicated neutropenia, a permitted effect from CXCR2 inhibition on bone-marrow trafficking, was excluded there were 25% grade 3/4 TRAEs and 12% DC [rash, transaminitis]). There was no infectious signal. At the 200 mg dose, the ORR was 21% in 19 evaluable pts (4 PR + 0 CR) and the DCR was 63% (8 SD + 4 PR). DCR significantly depended on SX-682 dose ( P vs. ≤100 mg): 0% (0/9) at ≤100 mg, 50% (3/6) at 150 mg ( P = 0.0440) and 63% (12/19) at 200 mg ( P = 0.0028). All 15 pts with disease control had progressed on anti-PD-1 and anti-CTLA-4. Median OS was longer in pts in the 200 mg cohort (14.7 months; 95% CI, 10.5 – NR [not reached], n = 31) than in pts treated with ≤100 mg SX-682 (7.4 months; 95% CI, 5.0 – NR; n = 10). Conclusions: SX-682 combined with pem had a tolerable safety profile and activity reflected by objective responses and clinically meaningful disease control in heavily pretreated mMEL pts with progression on anti-PD-1 and anti–CTLA-4. Clinical trial information: NCT03161431 .

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival and several are FDA-approved. Although not yet approved, neoadjuvant ICIs have also shown to improve event-free survival and remains an ongoing area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma, bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, and lifileucel, an autologous tumor-infiltrating lymphocyte therapy, for unresectable or metastatic melanoma are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAF V600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669